Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, South Korea.
Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
Cancer Immunol Immunother. 2024 Sep 5;73(11):215. doi: 10.1007/s00262-024-03805-3.
The detailed association between tumor DNA methylation, including CpG island methylation, and tumor immunity is poorly understood. CpG island methylator phenotype (CIMP) is observed typically in sporadic colorectal cancers (CRCs) with microsatellite instability-high (MSI-H). Here, we investigated the differential features of the tumor immune microenvironment according to CIMP status in MSI-H CRCs. CIMP-high (CIMP-H) or CIMP-low/negative (CIMP-L/0) status was determined using MethyLight assay in 133 MSI-H CRCs. All MSI-H CRCs were subjected to digital pathology-based quantification of CD3 + /CD8 + /CD4 + /FoxP3 + /CD68 + /CD204 + /CD177 + tumor-infiltrating immune cells using whole-slide immunohistochemistry. Programmed death-ligand 1 (PD-L1) immunohistochemistry was evaluated using the tumor proportion score (TPS) and combined positive score (CPS). Representative cases were analyzed using whole-exome and RNA-sequencing. In 133 MSI-H CRCs, significantly higher densities of CD8 + tumor-infiltrating lymphocytes (TILs) were observed in CIMP-H tumors compared with CIMP-L/0 tumors. PD-L1 TPS and CPS in CIMP-H tumors were higher than in CIMP-L/0 tumors. Next-generation sequencing revealed that, compared with CIMP-L/0 tumors, CIMP-H tumors had higher fractions of CD8 + T cells/cytotoxic lymphocytes, higher cytolytic activity scores, and activated immune-mediated cell killing pathways. In contrast to CIMP-L/0 tumors, most CIMP-H tumors were identified as consensus molecular subtype 1, an immunogenic transcriptomic subtype of CRC. However, there were no differences in tumor mutational burden (TMB) between CIMP-H and CIMP-L/0 tumors in MSI-H CRCs. In conclusion, CIMP-H is associated with abundant cytotoxic CD8 + TILs and PD-L1 overexpression independent of TMB in MSI-H CRCs, suggesting that CIMP-H tumors represent a typical immune-hot subtype and are optimal candidates for immunotherapy in MSI-H tumors.
肿瘤 DNA 甲基化（包括 CpG 岛甲基化）与肿瘤免疫之间的详细关联尚未完全清楚。CpG 岛甲基化表型（CIMP）通常在具有微卫星不稳定高（MSI-H）的散发性结直肠癌（CRC）中观察到。在这里，我们根据 MSI-H CRC 中的 CIMP 状态研究了肿瘤免疫微环境的差异特征。使用 MethyLight 测定法在 133 例 MSI-H CRC 中确定 CIMP-高（CIMP-H）或 CIMP-低/阴性（CIMP-L/0）状态。对所有 MSI-H CRC 进行基于数字病理学的 CD3+、CD8+、CD4+、FoxP3+、CD68+、CD204+、CD177+肿瘤浸润免疫细胞的定量分析，使用全切片免疫组化。使用肿瘤比例评分（TPS）和联合阳性评分（CPS）评估程序性死亡配体 1（PD-L1）免疫组化。使用全外显子组和 RNA 测序分析代表性病例。在 133 例 MSI-H CRC 中，与 CIMP-L/0 肿瘤相比，CIMP-H 肿瘤中 CD8+肿瘤浸润淋巴细胞（TIL）的密度明显更高。与 CIMP-L/0 肿瘤相比，CIMP-H 肿瘤中的 PD-L1 TPS 和 CPS 更高。下一代测序显示，与 CIMP-L/0 肿瘤相比，CIMP-H 肿瘤中 CD8+T 细胞/细胞毒性淋巴细胞的比例更高，细胞溶解活性评分更高，激活的免疫介导的细胞杀伤途径更多。与 CIMP-L/0 肿瘤相反，大多数 CIMP-H 肿瘤被鉴定为共识分子亚型 1，这是 CRC 的一种免疫原性转录组亚型。然而，在 MSI-H CRC 中，CIMP-H 与 CIMP-L/0 肿瘤之间的肿瘤突变负担（TMB）没有差异。总之，CIMP-H 与 MSI-H CRC 中丰富的细胞毒性 CD8+TIL 和 PD-L1 过表达相关，而与 TMB 无关，提示 CIMP-H 肿瘤代表一种典型的免疫热亚型，是 MSI-H 肿瘤免疫治疗的理想候选者。
